The present invention relates to a solid oral pharmaceutical composition comprising naloxone, or a pharmaceutically acceptable salt thereof, wherein the composition releases the active substance in a prolonged manner.
The present invention also relates to a solid oral pharmaceutical composition comprising naloxone, or a pharmaceutically acceptable salt thereof, for the treatment of opioid-induced constipation.
The present invention relates to a tablet comprising an opioid agonist, or a pharmaceutically acceptable salt thereof, as well as an opioid antagonist, or a pharmaceutically acceptable salt thereof, as active substances, wherein the tablet releases the active substances in a prolonged manner.
The present invention also relates to a solid oral pharmaceutical composition comprising naloxone, or a pharmaceutically acceptable salt thereof, for use in for the treatment of opioid-induced constipation.
Constipation is a major side effect of opioid analgesics administration. It is one of the most common side effects and is particularly predominant in long-term opioid administration therapies, occurring in approximately 85% of patients. In contrast to other opioid-induced side effects, opioid-induced constipation is a chronic phenomenon, the intensity of which does not decrease over the course of the treatment. The effect of the opioids on the gut mobility is probably due to binding of the opioids to the opioid receptors of the gastrointestinal tract, which are present there at a relatively high density.
The aim of the a therapy proposed here is to neutralize this peripheral side effect of opioids because opioid-induced constipation can be uncomfortable and very painful, and often leads to the discontinuation of the opioid-based therapy, and thus endangers the success of the treatment with the opioids. Since it can be assumed that the opioid-induced constipation is caused directly and locally over the entire intestine through binding to the opioid receptors, this side effect should be eliminated through the use of opioid antagonists. However, the use of opioid antagonists only makes sense if the antagonistic effect is limited to the intestine and does not cancel the main analgesic effect.
Naloxone is a suitable opioid antagonist for the treatment of opioid-induced constipation. Naloxone is rapidly and completely absorbed after oral administration and because the substance is subject to extensive first-pass metabolism, only small amounts of unmetabolised naloxone are available to the system. The vast majority of the applied substance is found in blood in the form of inactive or only mildly active metabolites such as naloxone-3-glucuronide or beta-6-naloxol. In suitable doses, naloxone is an ideal candidate for remedying opioid-induced constipation: in the intestine it is present as an active substance and can thus counter the paralysing effect of the opioid on the gastrointestinal tract, while after absorption it is largely metabolised during the first passage in the liver, and thereby becomes inactive. The analgesic effect of the opioids is thus not affected.
Since the paralysis does not only affect the duodenum and the upper part of the small intestine, but the entire gastrointestinal tract, the opioid-induced constipation cannot be treated successfully with a composition that releases the naloxone rapidly. WO 2011/117306 discloses a two-layer tablet, which in one layer contains an opioid agonist, and in another layer an opioid antagonist, wherein the tablet quickly releases both active substances. The advantage of this double-layer is to suppress the side effects of the opioid agonist, but it does not focus on suppression of the opioid-induced constipation.
The combined preparation Targin® is available on the market and comprises a mixture of the opioid agonist oxycodone in the form of a hydrochloric salt, and the opioid antagonist naloxone also in the form of a hydrochloric salt. In this preparation, the active substances are released in a prolonged manner. It is therefore suitable for the parallel treatment of pain and opioid-induced constipation. However, this monolithic formulation has the disadvantage that the release rates of the two active substances are fixed. Individualised treatments are therefore difficult to optimise.
In addition, infusion solutions available on the market for the treatment of opioid poisoning are only naloxone combined preparations, in which naloxone and the opiate are present in a fixed proportion to each other. However, for the treatment of opioid-induced constipation, it would be desirable to have single agent naloxone preparations, since this would allow administering naloxone both independently of the nature of the opiate and in variable doses. The desired quantity of naloxone could therefore be applied, which would lead to an optimal treatment. Naloxone single agent preparations are described in the patent literature, such as in WO 98/25613 A2. However, the release of naloxone from these compositions is dependent on the ambient pH in the gastrointestinal tract. A uniform application of naloxone to the entire gastrointestinal tract, and therefore an optimal treatment, are thus not possible with such products.